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J. Goossens
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-111 - Gene Polymorphisms in Thoracic Tumors Receiving Cisplatin-Pemetrexed (ID 810)
09:30 - 09:30 | Author(s): J. Goossens
- Abstract
Background:
Chemotherary combining cisplatin and the multitarget antifolate pemetrexed (ALIMTA[®]) is widely used in mesothelioma and metastatic non-squamous non-small cell lung cancer (n-sq NSCLC). Thymidylate synthase (TYMS) expression is recognized as a predictive marker of pemetrexed efficacy. Polymorphisms in TYMS and Excision repair cross-complementing (ERCC) genes have been associated with decreased tumour response to pemetrexed, and 5-10 Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been linked to increased toxicity to pemetrexed. The objective of this pilot study was to examine the feasibility and usefulness of testing gene polymorphisms for predicting pharmacodynamics of cisplatin-pemetrexed.
Methods:
This ancillary study (ALIMESO trial) was conducted on 21 patients (mean age 61, 15 men, 6 women) with malignant pleural mesothelioma (8 epithelioid, 2 sarcomatoid, 2 biphasic, 1 desmoplastic) or n-sq NSCLC (3 adenocarcinoma, 5 large-cell carcinoma) treated by cisplatin (75 mg/m[2]) plus pemetrexed (500 mg/m[2]) for 6 cycles (day 1 = day 22). Response to treatment was evaluated after 3 cycles (RECIST criteria). Toxicity was recorded according to CTC-AE classification. Gene polymorphisms were analyzed in all patients (blood DNA). TYMS polymorphisms in 5’UTR (28 bp repeats rs34743033 along with G>C mutation on 3R allele, rs11540151) were analyzed by PCR-RFLP and 6 bp deletion in 3’UTR (rs11280056) by PCR-electrophoresis. MTHFR C677T (rs1801133) and A1298C (rs1801131) were analyzed by sequencing. ERCC1 AAT118AAC (rs11615), ERCC2 Lys751Gln (rs13181), GSTP1 Ile105Val (rs1695) and Ala114Val (rs1138272) were analyzed by PCR-RFLP.
Results:
13 patients (62%) were evaluable for response (8 patients not assessable due to either no chemo or <3 cycles). ORR was 46% (6PR, no CR) and DCR was 100%. 20 patients (95%) were evaluable for toxicity. 78 chemotherapy-related adverse events were reported with 17 (22%) grade 3/4 (2 anemia, 7 neutropenia, 5 thrombocytopenia, 1 renal failure, 1 asthenia, 1 nausea). There was no toxic death. Chemotherapy was stopped after 3 cycles for 2 patients. Homozygous and heterozygous deletion in 3’UTR of TYMS was observed in 1 and 9 patients, respectively. For TYMS 5’UTR, 13 patients belong to class 2 (2R/2R, 2R/3RC or 3RC/3RC), 6 belong to class 3 (2R/3RG or 3RG/3RC) and one belong to class 4 (3RG/3RG). Other genotypes were as follows. GSTP1 codon 105: 10 Ile/Val and 4 Val/Val; GSTP1 codon 114: 1 Ala/Val; ERCC1 codon 118: 10 C/T and 4 C/C; ERCC2 codon 751: 12 Lys/Gln and one Gln/Gln; MTHFR C677T: 10 C/T and 3 T/T; MTHFR A1298C: 8 A/C and 3 C/C. There was no correlation between any gene polymorphisms and response or G3-4 toxicity. Of note, among the 6 patients homozygous for rare MTHFR alleles (i.e. 677TT or 1298CC), 4 exhibited a high-grade (grade 3/4) haematological toxicity.
Conclusion:
Present results suggest that gene polymorpshism analysis is feasible in the context of pharmacodynamics predictivity. From this limited number of patients, a trend was observed between MTHFR genotype and haematological toxicity. These preliminary data need to be confirmed on a larger set of patients with thoracic tumors treated by cisplatin/pemetrexed.
